Aspirin-intolerant Patients Research Articles

Dengzhan Shengmai capsule versus Aspirin in the treatment of carotid atherosclerotic plaque: A single-centre, non-inferiority, prospective, randomised controlled trial

BackgroundAspirin is an effective antiplatelet agent for the treatment of carotid atherosclerosis. However, the high risk of bleeding events associated with the drug makes it necessary to seek a safer alternative, with similar or more efficacy than aspirin. Dengzhan Shengmai (DZSM) capsules have been widely used to treat carotid atherosclerosis, and if proven to be non-inferior to aspirin, it may be preferable over the latter for carotid atherosclerosis treatment due to its numerous advantages. We conducted a randomised trial to test the non-inferiority of DZSM to aspirin for the treatment of carotid atherosclerotic plaques. MethodsWe performed a single-centre, prospective, open-label, randomised non-inferiority trial. Patients with carotid atherosclerotic plaques were enrolled and randomly assigned (1:1) to receive either DZSM capsules or aspirin. The follow-up period was 12 months. The primary outcome was the mean change in carotid intima-media thickness (IMT). Secondary outcomes included ischaemic events, rate of lumen stenosis, lipid levels, and plaque scores, length, counts, and vulnerability. Adverse events and laboratory test results were recorded as safety outcomes. The non-inferiority of DZSM was demonstrated when the lower limit of the one-sided 97.5% confidence interval (CI) of the difference in IMT between groups was more than -0.06 mm (margin of non-inferiority). This trial has been registered at ClinicalTrials.gov (CHiCTR1900021365). ResultsFrom 1 April 2019 to 30 September 2019, 150 patients were enrolled, and there was no statistical difference in demographics between the groups. Intention-to-treat analysis showed that the decrease in IMT(∆IMT) was 0.216 ± 0.160 and 0.225 ± 0.149 mm in the DZSM and aspirin groups, respectively. The one-sided 97.5% CI for the difference between ∆IMTs was (-0.0593, +∞). The non-inferiority of DZSM was demonstrated (Pnon-inferiority = 0.0234). There was no significant difference in the incidence of ischaemic events between the groups (P = 1.0). The DZSM group had significantly reduced plaque scores (P < 0.0001), length (P < 0.0001), and counts (P < 0.0001), and improved plaque vulnerability (P < 0.0001). The DZSM group also had reduced levels of low-density lipoprotein cholesterol (LDL-C) (P < 0.0001). Finally, the DZSM group had a lower incidence of total adverse events (14.7% vs. 28%, P = 0.046), especially gastrointestinal discomfort (5.3% vs. 16%, P = 0.034). Although there was no significant difference in bleeding events (0 vs. 5.3%, P = 0.120), the DZSM group tended to have a lower incidence. ConclusionThis trial demonstrated that DZSM was not inferior, in efficacy, to aspirin in treating carotid atherosclerotic plaques, and was found to be superior to aspirin in terms of safety. This study provides a new approach for treating carotid plaques, especially in aspirin-intolerant patients.

Comprehensive Analysis of Nasal Polyps Reveals a More Pronounced Type 2 Transcriptomic Profile of Epithelial Cells and Mast Cells in Aspirin-Exacerbated Respiratory Disease.

Chronic rhinosinusitis with nasal polyps is affecting up to 3% of Western populations. About 10% of patients with nasal polyps also suffer from asthma and intolerance to aspirin, a syndrome called aspirin-exacerbated respiratory disease. Although eosinophilic inflammation is predominant in polyps of both diseases, phenotypic differences in the tissue-derived microenvironment, elucidating disease-specific characteristics, have not yet been identified. We sought to obtain detailed information about phenotypic and transcriptional differences in epithelial and immune cells in polyps of aspirin-tolerant and intolerant patients. Cytokine profiles in nasal secretions and serum of patients suffering from aspirin-exacerbated respiratory disease (n = 10) or chronic rhinosinusitis with nasal polyps (n = 9) were assessed using a multiplex mesoscale discovery assay. After enrichment for immune cell subsets by flow cytometry, we performed transcriptomic profiling by employing single-cell RNA sequencing. Aspirin-intolerant patients displayed significantly elevated IL-5 and CCL17 levels in nasal secretions corresponding to a more pronounced eosinophilic type 2 inflammation. Transcriptomic profiling revealed that epithelial and mast cells not only complement one another in terms of gene expression associated with the 15-lipoxygenase pathway but also show a clear type 2-associated inflammatory phenotype as identified by the upregulation of POSTN, CCL26, and IL13 in patients with aspirin-exacerbated respiratory disease. Interestingly, we also observed cellular stress responses indicated by an increase of MTRNR2L12, MTRNR2L8, and NEAT1 across all immune cell subsets in this disease entity. In conclusion, our findings support the hypothesis that epithelial and mast cells act in concert as potential drivers of the pathogenesis of the aspirin-exacerbated respiratory disease.

Expression of Transcript Variants of PTGS1 and PTGS2 Genes among Patients with Chronic Rhinosinusitis with Nasal Polyps.

To date, there has been no reliable test to identify unfavorable course of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), especially in aspirin intolerant patients. The research aimed to analyze the expression of transcript variants of PTGS1 and PTGS2 genes in the pathobiology of the disease. The study was performed on 409 adult patients: 206 CRSwNP patients including 44 (21.36%) aspirin intolerant patients and 203 healthy volunteers in the control group. Transcript variants of the PTGS1 and PTGS2 genes named as follows: COX1.1 for NM_000962, COX1.2 for NM_080591, COX1.3 for NM_001271165.1, COX1.4 for NM_001271368.1, COX1.5 for NM_001271166.1, COX2.1 for NM_000963.3, COX2.2 for AY_151286 and COX2.3 for BQ_722004 were confirmed using direct sequencing and quantified using targeted qPCR. The coexistence of all examined transcript variants in the study and the control group and significant differences between both were found. In aspirin sensitive patients, the levels of COX1.2, COX1.3, COX1.4 and COX1.5 isoforms were higher compared to aspirin-tolerant patients. The severity of symptoms was bigger in patients with higher expressions of variants: COX1.1 (R with dCt = −0.134; p = 0.0490), COX1.3 (R = −0.1429; p = 0.0400) and COX1.5 (Rs = −0.1499; p = 0.032). The expression of COX1.1 (Rs = −0.098; p = 0.049) and COX1.5 (Rs = −0.141; p = 0.043) isoforms increased with polyposis advancement in endoscopy. With the CT extent of sinuses opacification, COX1.1 isoform also significantly increased (Rs = −0.163; p = 0.020). The isoforms COX1.3, COX1.4, COX1.5 and COX2.1 may promote milder CRSwNP course. On the contrary, the variants COX1.1, COX1.2 and COX2.2 may be involved in a more aggressive disease.

Montelukast Has no Impact on the Systemic Production of TGFβ-1 in Patients with Nasal Polyposis Associated with Aspirin Intolerance.

Introduction Nasal polyposis is a disease characterized by a mechanical dysfunction of the nasal mucosa, closely related to the unique makeup of its extracellular matrix, which develops as the result of an anomalous tissue remodeling process. Transforming growth factor beta 1 (TGF-β1) is reduced not only in the nasal polypoid tissue, but also in the plasma of aspirin-intolerant patients. These patients exhibit an imbalance in the production of eicosanoids characterized by an increase in leukotrienes. Thus, it is important that the relationship between the production of leukotrienes and TGF-β1 be assessed. Objective To evaluate the effects of the cysteinyl leukotriene (CysLT) receptor antagonist montelukast on the systemic production of TGF-β1 in patients with nasal polyposis, with or without concomitant aspirin intolerance. Methods The sample comprised 48 individuals with diagnosis of nasal polyposis and 15 healthy controls for comparison of the baseline TGF-β1 levels in the peripheral blood and after treatment with CysLT receptor antagonist montelukast in the nasal-polyposis group. Results There was no difference in the change in TGF-β1 levels after the treatment with montelukast in the subgroup of patients with polyposis and asthma ( p = 0.82) and in the subgroup with polyposis, asthma, and aspirin intolerance ( p = 0.51). Conclusion we found no impact of the therapy with a leukotriene receptor blocker on the production of TGF-β1, making the antileukotriene therapy a highly questionable choice for the treatment of nasal polyposis, particularly from the standpoint of seeking to modify the remodeling process in this disease.

Aspirin desensitization procedures in aspirin intolerant patients: a neglected topic in the ESC 2019 Chronic Coronary Syndrome guidelines.

Aspirin desensitization procedures in aspirin intolerant patients: a neglected topic in the ESC 2019 Chronic Coronary Syndrome guidelines.

Combination Therapy with Dipyridamole and Clopidogrel for Secondary Stroke Prevention in Aspirin-Intolerant Patients After Myocardial Infarction: Results of a Nationwide Case-Control Study.

Background and PurposeCombination therapy with dipyridamole and clopidogrel in stroke prevention and long-term outcomes in aspirin-intolerant patients with acute myocardial infarction (AMI) and previous stroke are unknown. This nationwide study analyzed the impact of dipyridamole and clopidogrel on secondary stroke prevention and long-term outcomes in aspirin-intolerant stroke patients after AMI.MethodsThis was a nationwide, case-control study involving 186,112 first AMI patients, 78,607 of whom had a previous history of stroke. In the final analysis, we included 4637 patients taking clopidogrel alone and 208 patients using a combination of clopidogrel and dipyridamole.ResultsThe 12-year survival rate was not different between clopidogrel and clopidogrel–dipyridamole groups (log-rank p = 0.6247). Furthermore, there were no differences in event-free survival after stroke (log-rank p = 0.6842), gastrointestinal (GI) bleeding (log-rank p = 0.9539), or intracerebral hemorrhage (ICH; log-rank p = 0.6191) between the two groups. Dipyridamole did not contribute significantly to AMI survival (hazard ratio 0.98, 95% confidence interval 0.84–1.15), and did not show benefits in any of the subgroups regardless of sex, age (younger or older than 75 years), comorbidities, percutaneous coronary intervention, or medications.ConclusionNo differences were observed in the 12-year survival rate between clopidogrel and clopidogrel–dipyridamole groups. The two groups had balanced event-free survival in recurrent stroke, ICH, GI bleeding, and myocardial infarction.

CCL4 Levels Differ between Aspirin-Tolerant and Aspirin-Intolerant Patients with Asthma

Aspirin-exacerbated respiratory disease (AERD) is an asthma phenotype characterized by nasal polyps, chronic hypertrophic eosinophilic sinusitis, asthma, and sensitivity to aspirin. Unawareness of this disease by patients and their physicians may have serious consequences because of the risk of near-fatal asthma. Its confirmative diagnosis can be established only by provocative aspirin challenge, which represents a potential risk for patient health. Purpose: Because CCL4 plays an important role in several pulmonary conditions, we tested its immunoreactivity in nasal lavages and sera from control subjects, and from aspirin-sensitive and non-aspirin-sensitive patients. Method: Immunoreactivity of CCL4 was measured in serum and nasal lavages from 30 healthy controls (HC), 23 patients with AERD, and 20 patients with aspirin-tolerant asthma (ATA). Additionally, a serum biobank contained sera from 90 HC, 83 patients with AERD, and 69 patients with ATA was employed. Results: The serum immunoreactivity of CCL4 could distinguish both types of asthma phenotypes. Conclusion: CCL4 may play an unexpected role in thephysiopathology of AERD.

Altered Inhibitory Function of the E-Type Prostanoid Receptor 4 in Eosinophils and Monocytes from Aspirin-Intolerant Patients

Prostaglandin (PG) E₂ has been implicated in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). E-type prostanoid (EP) receptor 4 is known to confer inhibitory signals to eosinophils and monocytes, amongst others. In this study, we investigated whether the responsiveness of eosinophils and monocytes to PGE₂ and EP4 receptor activation is altered in AERD patients. While the expression of the EP4 receptor in eosinophils was unaltered in AERD patients, inhibition of eosinophil chemotaxis by PGE₂ or the EP4 agonist CAY10598 was less pronounced in AERD patients as compared to healthy control subjects. In monocytes, we found no changes in basal or lipopolysaccharide (LPS)-stimulated PGE₂ synthesis, but the response to EP4 receptor activation with respect to inhibition of LPS-induced tumor necrosis factor-α release was reduced in AERD patients, especially in the presence of aspirin (acetylsalicylic acid). Our data point towards a decreased sensitivity of inhibitory EP4 receptor that may play a role in AERD.

Role of frontal sinus surgery in nasal polyp recurrence

Patients with aggressive nasal polyp recurrence form an important subgroup of patients with refractory sinus disease. The objectives of this study were to establish patterns of polyp recurrence and evaluate the effect of frontal sinus surgery (Draf 2a vs. Draf 3) on polyp recurrence. Retrospective cohort study reviewing 338 consecutive operations. Polyp recurrence was defined according to the Lund-Kennedy mucosal edema score. Survival analysis methods were used for statistics. After complete sphenoethmoidectomies, Draf 2a frontal sinusotomies, and middle meatal antrostomies persistent polyp recurrence occurred in 19.8% of patients after 6 months and increased to 22.7% of patients after 12 months. Polyps first recurred in the area of the frontal sinus/ostium (55%) followed by the ethmoids (38%). Asthma and aspirin sensitivity were the most important variables affecting recurrence (hazard ratios, 1.71, 1.79, respectively; P < .05) The Draf 3 procedure was a significant factor in reducing recurrence, especially in asthma and aspirin intolerant patients. The overall revision rate was 18% (follow-up duration >12 months, median = 29 months), with a 37% revision rate in the FESS group versus 7% in the Draf 3 group (P < .001). Survival analysis showed that the Draf 3 significantly reduced the risk of revision (hazard ratio = 0.258, P = .0026). Nasal polyposis is characterized by a high rate of recurrence. The presence of asthma or aspirin intolerance leads to more aggressive recurrence, and in these patients the Draf 3 drillout procedure becomes a good option for improved long-term outcomes and reducing the need for revision surgery.

Low SPINK5 expression in chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is a multifactorial disease that probably arises as a result of genetic diversity and environmental factors. SPINK5 is a serine protease inhibitor, which is supposed to be an important regulator of epithelial barrier maintenance. The role of SPINK5 polymorphisms and expression in CRS, especially in individuals with aspirin intolerance, is unclear. SPINK5 single-nucleotide polymorphisms (SNPs) and SPINK5 expression levels were correlated with CRS without (CRSsNP) and with nasal polyps (CRSwNP), aspirin intolerance, asthma, and allergies. One hundred four nasal tissue samples, 15 from patients with CRSsNP, 59 from patients with CRSwNP, and 30 from healthy controls of the inferior turbinate, were analyzed for their SPINK5 status. Genotypes of four SPINK5 single nucleotide polymorphism (SNPs; G1258A, G2475T, A2915G, and A1103G), as well as SPINK5 mRNA expression levels, were determined by polymerase chain reaction. No correlation between any SPINK5 SNP and CRSsNP, CRSwNP, or allergies and asthma was observed. The heterozygous SNPs G1258A and A1103G were observed more frequently in aspirin-intolerant patients; the homozygous (A/A) genotype of SNP 1258 and the homozygous (G/G) genotype SNP 1103 were less frequent. There was no correlation between the analyzed SNPs and the level of SPINK5 expression. It was noted that in individuals with CRSwNP, aspirin intolerance, and allergies, SPINK5 expression was lowered. G1258A and A1103G polymorphisms are distinctive for the aspirin intolerance syndrome. Lowered SPINK5 expression might be a contributing factor leading to CRS, and appears to be characteristic for patients suffering from aspirin intolerance and from allergies.

Vascular Endothelial Growth Factor Expression in Nasal Polyps of Aspirin-Intolerant Patients

To study differences between aspirin-tolerant patients and aspirin-intolerant patients concerning vascular endothelial growth factor (VEGF) expression. Recent publications strongly suggest the involvement of VEGF and its receptors in the pathophysiologic process of nasal polyps. We subjected 43 polyp specimens to semiquantitative immunohistochemical analysis. We quantified VEGF and its receptors (Flk, Flt, and neuropilin) in all samples. To gain insight into potential VEGF-mediated cellular responses, we determined proliferative (Ki67) and apoptotic (caspase 3) indices. Polyp samples were obtained from 22 aspirin-intolerant patients and from 21 aspirin-tolerant patients, and control specimens were obtained from 24 subjects with healthy nasal respiratory mucosa. Laboratory; Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Expression levels of VEGF, VEGF receptors. and proliferative and apoptotic indices. We found higher expressed levels of VEGF and neuropilin and stronger proliferation in nasal polyps from aspirin-tolerant and aspirin-intolerant patients compared with controls. In polyps from aspirin-intolerant patients, VEGF was expressed at considerably higher levels compared with those from aspirin-tolerant subjects. Apoptotic activity remained unchanged in all 3 groups. Nasal polyps from aspirin-tolerant and aspirin-intolerant patients are characterized by strong proliferation and high levels of VEGF and neuropilin expression. Nasal polyps from aspirin-intolerant patients show distinctly increased VEGF levels. The relevance of these findings for future therapeutic approaches is yet to be determined.

Strategy for NSAID administration to aspirin-intolerant asthmatics in combination with PGE2 analogue: a theoretical approach

Aspirin-induced asthma (AIA) is a severe inflammatory disease, which affects aspirin-intolerant patients after ingestion of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). In this article, a mathematical model describing arachidonic acid metabolism and its interaction with NSAIDs, is used to study the strategy for safe managing of NSAIDs to AIA patients. Three different AIA patient populations are taken into consideration. First, the values of aspirin and ibuprofen limiting doses that might induce symptoms of AIA are calculated and compared to experimentally observed threshold doses to enlighten which AIA patient population is susceptible to aspirin and ibuprofen. Second, the methodology of NSAID administration is studied on AIA populations susceptible to aspirin and ibuprofen by using 1,000 mg dose of aspirin and 200 or 400 mg dose of ibuprofen followed by PGE(2) analogue dosing. Our model results show that successive doses of PGE(2) analogue applied at appropriate time after aspirin or ibuprofen ingestion would enable administration of both NSAIDs to AIA patients. PGE(2) analogue doses and the corresponding times of their applications are calculated. The model is also used to estimate the duration of symptoms of AIA for different aspirin and ibuprofen doses.

Role of expression of prostaglandin synthases 1 and 2 and leukotriene C4 synthase in aspirin-intolerant asthma: a theoretical study

Altered expressions of the key enzymes in arachidonic acid (AA) metabolism, prostaglandin synthase 1 and 2 and cysteinyl leukotriene C(4) synthase, are of importance in understanding aspirin-induced asthma. We propose a mathematical model of AA metabolism and its interaction with non-steroidal anti-inflammatory drugs (NSAIDs). Model simulations depict the impact of modified expressions of the above enzymes on the time dependent synthesis of cysteinyl leukotrienes and anti-inflammatory prostaglandins before and during NSAID exposure in different model states describing healthy humans as well as aspirin-tolerant and -intolerant asthmatics. The results are compared and evaluated with experimental data taken from the literature. Our results identify the decreased expression of prostaglandin H synthase 1 and increased expression of leukotriene C(4) synthase as the key elements in AA metabolism that contribute to increased leukotriene C(4) and decreased anti-inflammatory prostaglandins after NSAID dosing in aspirin-intolerant patients. On the other hand, the decreased expression of prostaglandin H synthase 2 implies permanently increased leukotriene C(4) and lowers the sensitivity to increased drug doses. The model is used for identification of susceptible patient populations for aspirin and ibuprofen, and for identification of critical aspirin doses that might induce bronchoconstriction.

Infectious diarrhea: when to test and when to treat

<h3>BACKGROUND</h3> Nasal provocation tests with lysine-aspirin have recently been introduced for assessment of aspirin intolerant asthma. A study was undertaken to evaluate the usefulness of acoustic rhinometry, a new non-invasive technique, in the diagnosis of aspirin intolerant asthma/rhinitis. <h3>METHODS</h3> Fifteen patients with aspirin intolerant asthma/rhinitis (nine women, mean (SD) age 54.7 (14) years), eight patients with aspirin tolerant asthma/rhinitis (three women, mean (SD) age 52.6 (7.8) years), and eight healthy subjects (two women, mean (SD) age 32.5 (9.7) years) were studied. All subjects were challenged with saline (0.9% NaCl) and 25 mg lysine acetylsalicylic acid (L-ASA) instilled into each nostril of the nose on two separate days. The clinical response was evaluated based on nasal symptoms (sneezes, itching, secretion and blockage). The nasal response was measured by acoustic rhinometry. Symptoms and rhinometry curves were recorded at 10 minute intervals for three hours, one hour before challenge and two hours after challenge. <h3>RESULTS</h3> L-ASA challenge induced a significant increase in symptoms in patients with aspirin intolerant asthma/rhinitis. No differences in the clinical response were detected in those with aspirin tolerant asthma/rhinitis or healthy subjects. L-ASA challenge induced a significant decrease in nasal volume measured by acoustic rhinometry in aspirin intolerant patients. No differences were detected between the challenges in aspirin tolerant patients. If a 25% decrease in nasal volume is taken as the cut off point, the specificity of the test was 94% and the sensitivity reached 73%. The nasal challenge was well tolerated by all subjects. <h3>CONCLUSION</h3> Acoustic rhinometry may be used to study the nasal response to L-ASA. Nasal challenge with L-ASA is safe and can be used as a diagnostic test even in asthmatic patients with severe bronchial obstruction.

Mediators of inflammation in nasal lavage from aspirin intolerant patients after aspirin challenge

The pathogenetic mechanisms underlying development of persistent inflammation in aspirin (ASA) intolerance are not fully understood. The aim of this study was to determine levels of MCP-3, RANTES, eotaxin, Il-5 and Il-3 in aspirin intolerant asthmatics (AIA) after nasal lysine-aspirin (Lys-ASA) challenge. Twenty AIA and 10 aspirin tolerant controls (ATC) were challenged with saline or 14.4mg of Lys-ASA. Lys-ASA challenge induced clinical symptoms and influx of eosinophils and basophils only in AIA group. Statistically significant higher levels of MCP-3 and RANTES were found in lavages from AIA as compared with ATC (p<0.05 in all time points). Before challenge the average level of MCP-3 was 86.95pg/ml in AIA and 47.61pg/ml in ATC, RANTES levels were 34.20pg/ml in AIA and 17.21pg/ml in ATC and did not change after the challenge in both group. The mean eotaxin's level was 11.01pg/ml in AIA and 8.03pg/ml in ATC before and increased to 20.06, 26.22pg/ml (4 and 24h in AIA) as compared to 10.51, 14.76pg/ml (4 and 24h in ATC) after the challenge (p<0.05). Interleukin-3 and Il-5 were not detectable. The highest inhibition of eosinophils' chemotaxis was induced by anti-eotaxin (47% of inhibition), followed by anti-RANTES (29%), anti-MCP-3 (19%) and anti-Il-5 (9%). In summary, we found that persistent inflammation in AIA patients is characterized by overproduction of MCP-3 and RANTES. Lack of increase in MCP-3 and RANTES levels after Lys-ASA challenge suggest that those mediators are involved in chronic rather than acute phase of ASA induced inflammation.

Lipoxin A4 generation is decreased in aspirin‐sensitive patients in lysine‐aspirin nasal challenge in vivo model

Lipoxins represent a group of lipoxygenase derived eicosanoids which, in contrast to leukotrienes, are potent anti-inflammatory mediators. The aim of our study was to determine lipoxin A(4) (LXA(4)) and leukotriene C(4) (LTC(4)) levels in nasal lavages after intranasal challenge with aspirin in aspirin intolerant (AIA) in comparison to aspirin tolerant (ATA) asthmatics and after allergen challenge in patients suffering from allergic rhinitis. Twelve AIA, 8 ATA and 20 allergic patients were challenged with placebo, 16 mg of lysine-aspirin (Lys-ASA) or allergen (grasses). Nasal lavages were collected and eicosanoids' levels were determined using ELISA. Clinically positive Lys-ASA challenge in AIA resulted in influx of leukocytes (eosinophils and basophils) to nasal secretions and increase of LTC(4) to 106.82 pg/ml (P < 0.05 vs baseline (26.58 pg/ml)) on first hour after the challenge. We did not observe any differences in LTC(4) level before and after ASA challenge in ATA. In AIA group the mean level of LXA(4) was 43 +/- 21.5 pg/ml after placebo and decreased in 2 h after Lys-ASA challenge (29 +/- 17 pg/ml, P = 0.015). We found an increase in LXA(4) in ATA after ASA provocation as compared to placebo (33 +/- 16 pg/ml vs 52 +/- 31 pg/ml, P = 0.046). In atopic patients baseline level of LXA(4) was 33.49 +/- 16.95 pg/ml with no difference after the clinically positive allergen challenge (36.22 +/- 13.26 pg/ml, P = 0.23). Results of our study confirm that AIA have diminished LXs' biosynthesis capacities in vivo after ASA challenge. Taking into consideration anti-inflammatory properties of lipoxins this phenomenon may be partially responsible for the development of chronic inflammation in AIA patients.

Aspirin-Induced COX-2 Overexpression in Monocytes of Aspirin-Intolerant Patients

Background: We hypothesize that alternate regulation of cyclooxygenase-2 (COX-2) may predispose patients to aspirin-induced exacerbations.Therefore, we want to examine the dynamics of COX-2 up-regulation in whole blood monocytes in the presence and absence of aspirin. Methods: COX-2 expression was evaluated by flow cytometry through intracellular staining of whole blood monocytes with antiCOX-2 antibodies. Enzyme up-regulation was monitored after in vitrostimulation with lipopolysaccharide (LPS) and/or aspirin in 19 aspirin-intolerant (AI) patients (8 aspirin-sensitive asthmatics and 11 urticaria-angioedema patients) and 14 healthy controls. Results: We found significantly higher COX-2 expression levels after stimulation with LPS and aspirin (mean 78.8, range 44.9–92.3; p = 0.0002) in comparison to LPS alone (mean 65.9%, range 33.6–82.6) in AI patients. A comparable, but lower up-regulation was also observed after aspirin stimulation alone (median 2.1%, range 0.5–15.9; p = 0.004) in comparison with baseline values (median 1%, range 0.1–5.4). There was no significant difference in COX-2 expression between LPS and aspirin stimulation (mean 61.8%, range 26.8–89.2; p = 0.09) and LPS stimulation (mean 55.5%, range 28.1–74.3) nor between aspirin stimulation alone (median 0.5%, range 0–8.6; p = 0.8) and baseline values (median 0.4%, range 0–5.4) in healthy control subjects. Conclusions: The main finding of this study is that COX-2 appears to be differentially regulated in aspirin-sensitive patients. What is really new is the observation that aspirin and LPS increase COX-2 expression on blood monocytes of AI asthmatics, a finding in contrast with the lack of an effect of the same stimuli on COX-2 expression on monocytes from healthy subjects.

Prevention of secondary stroke and transient ischaemic attack with antiplatelet therapy: the role of the primary care physician role

Stroke risk is heightened among patients who have had a primary stroke or transient ischaemic attack (TIA). The primary care physician is in the best position to monitor these patients for stroke recurrence. Because stroke recurrence can occur shortly after the primary event, guidelines recommend initiating antiplatelet therapy as soon as possible. Aspirin, with or without extended-release dipyridamole (ER-DP), and clopidogrel are options for such patients. Low-dose aspirin (75-150 mg/day) has the same efficacy as higher doses but with less gastrointestinal bleeding. Clopidogrel remains an option for prevention of secondary events and may benefit patients with symptomatic atherothrombosis, but its combined use with aspirin can harm patients with multiple risk factors and no history of symptomatic cerebrovascular, cardiovascular or peripheral vascular disease. Low dose aspirin is effective in secondary stroke prevention. Trials assessing aspirin plus ER-DP have shown that the combination is more effective than aspirin monotherapy in preventing stroke, with efficacy increasing among higher risk patients, notably those with prior stroke/TIA. Clopidogrel does not appear to have as much advantage over aspirin in secondary stroke prevention as aspirin plus ER-DP. Smoking cessation and cholesterol, blood glucose and blood pressure control are also important concerns in preventing recurrent stroke. In choosing pharmacological therapy, the physician must consider the individual patient's risk factors and tolerance, as well as other issues, such as use of aspirin among patients with ulcers. Antiplatelet therapy is effective in secondary stroke prevention. Low dose aspirin can be used first-line, but aspirin plus ER-DP improves efficacy. Clopidogrel is another option in secondary stroke prevention, especially for aspirin-intolerant patients, but it appears to have less advantage over aspirin than aspirin plus ER-DP, and its combined use with aspirin has only marginally better efficacy and increased bleeding risk.

Intranasal lysine-aspirin administration decreases polyp volume in patients with aspirin-intolerant asthma

Nasal polyposis associated with aspirin-intolerant asthma tends to be difficult to control, with frequent recurrences. We examined the effect of intranasal lysine-aspirin administration on resistant nasal polyps of asthmatic, aspirin-intolerant patients, when used in addition to routine therapy. Thirteen patients with asthma and intolerance to aspirin were recruited. All but one had undergone numerous polypectomies and were uncontrolled on standard therapy with intranasal corticosteroids, leukotriene receptor antagonists and nasal douching. Aspirin treatment involved one drop (100 microl) of 30 mg/ml lysine-aspirin solution to each nostril, initially daily, increased every two or three days up to a maximal of 18 drops (54 mg lysine-aspirin) a day. Nasal symptoms, nitric oxide level, nasal inspiratory peak flow rate, peak expiratory flow rate and nasendoscopic grading were assessed prior to therapy and three months later. We also compared the change in endoscopic polyp scores during three months of lysine-aspirin administration with the changes which had occurred during the three months prior to administration (during which time other therapies had been identical). Nasal blockage symptoms tended to decrease; other nasal symptoms were unchanged. Significant changes were seen in nasal inspiratory peak flow rate (103.3 +/- 18.9 and 140.0 +/- 16.7 l/min before and after aspirin, respectively; p = 0.014), but not in peak expiratory flow rate (438.7 +/- 33.4 and 440.0 +/- 28.4 l/min before and after aspirin, respectively; p = 0.700). Nasal nitric oxide levels rose significantly (in both sides, p = 0.028). Expired chest nitric oxide levels did not change. Nasal polyp scores on nasendoscopic examination were significantly reduced (right side, p = 0.027; left side, p = 0.018). Compared with the preceding three months, adding intranasal lysine-aspirin application had the effect on decreasing nasal polyp volume (right side, p = 0.031; left side, p = 0.016). This open study suggests that intranasal lysine-aspirin administration reduces nasal polyp volume in aspirin-intolerant patients, without any adverse affect on concomitant asthma. This was a preliminary study and should be followed by a placebo-controlled, double-blind trial.

Endothelial L-Selectin Ligands in Sinus Mucosa during Chronic Maxillary Rhinosinusitis

Chronic rhinosinusitis is characterized by persistent inflammation of the nasal and paranasal mucosa with numerous emigrated leukocytes. L-selectin on leukocytes and its endothelial glycosylated ligands initiate organ-specific leukocyte infiltration into inflamed tissues. The purpose of this study was to evaluate the endothelial expression of functionally active endothelial L-selectin ligands, sulfated sialyl Lewis x, in maxillary sinus mucosa from patients with chronic rhinosinusitis and from normal control subjects. Maxillary sinus mucosa specimens (116) were obtained surgically and immunohistochemically stained with monoclonal antibodies detecting sialyl Lewis x or sulfated extended core 1 lactosamines. The severity of the inflammation was determined by intraoperative endoscopic findings, computed tomography scans, and histopathologic assessment of the specimens. The percentage of vessels expressing endothelial sulfated sialyl Lewis x epitopes increased during chronic rhinosinusitis compared with uninflamed control tissue, especially in patients with additional allergic rhinitis, and decreased in specimens from aspirin-intolerant patients with preoperative oral corticosteroid treatment. In addition, the expression level of endothelial sulfated sialyl Lewis x epitopes and the number of mucosal eosinophils correlated with the severity of the inflammation, and decreased in specimens taken 9 months postoperatively compared with intraoperative samples, especially in patients with intranasal corticosteroid treatment. Our results suggest that functionally active L-selectin ligands might guide leukocyte traffic into maxillary sinus mucosa preferentially in patients with severe findings of chronic maxillary rhinosinusitis, thus leading to aggravation of the inflammation.